Although chemotherapy and radiation therapy have been attempted in either adjuvant or palliative treatments, more effective adjuvant therapy is needed for colon cancer patients. Malignant tumor cells are clearly distinguished from normal cells by their chaotic proliferation due to a serious disorder of the cell cycle regulatory machinery. Cell cycle inhibitors or modulators that halt uncontrollable tumor growth are regarded as highly promising new therapeutic agents on human cancers. Recent studies have shown that the G1 phase of the cell cycle is an important period where various signals interact to determine the proliferation, quiescence, differentiation or apoptosis of cells (Science 1996; 274:1672-7). The use of chemical agents to induce differentiation of tumor cells has received widespread attention as a potentially less toxic cancer therapy.
Adamantane derivatives possess several attractive pharmacological activities such as antibacterial, antifungal, antiviral and anticancer effects (J Med Chem 1975; 18:713-21, General Physiology & Biophysics 1986; 5:61-75). Therefore, it is considered that the adamantane derivatives are highly promising candidates in drug design (European Journal of Pharmacology 1991; 206:297-300, Biochemical Pharmacology 1987; 36:481-7). For example, the aminoadamantane derivatives memantine (1-amino-3,5-dimethyl adamantane) and amantadine (1-aminoadamantane) are uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists which have been used clinically in the treatment of dementia and Parkinson's disease for several years without serious side effects (European Journal of Pharmacology 1991; 206:297-300, Biochemical Pharmacology 1987; 36:481-7). It is found in our previous study that N-1-adamantylmaleimide (AMI) and dimethyladamantylmaleimide (DMAMI) induce apoptosis and inhibit the growth of the human gastric (SC-M1) and colon (Colo 205) cancer in SCID mice, respectively (Anti-Cancer Drugs 2002; 13:533-43, Anti-Cancer Drug Design 1998; 13: 779-96). In a recent study, we have characterized the anticancer activities of diaminodiamantane derivatives from the 60 human cancer cell lines in NCI Anticancer Drug Screen, and evaluated the structure-activity relationship for the diaminodiamantane derivatives. It is found that 1,6-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)diamantane (DPD) exhibited marked anticancer activities on the colon cancer cell lines (Anti-cancer Drug 2004; 15: 277-86). We have recently demonstrated that administration of DPD induced G0/G1 arrest and differentiation in human colon cancer cells (Br. J Cancer 2003; 89: 1995-2003). DPD also has in vivo anticancer activity on human colon cancer cells xenografts with no obvious acute toxicity.
Adamantane and diamantane are closely analogous polycyclic alkane with the structure of three and six fused cyclohexane rings, respectively. The present invention provides the preparation methods for the diaminophenyladamantane derivatives, including 1,3-bis(4-aminophenyl)adamantane (1,3-DPANH2), 2,2-bis(4-aminophenyl)adamantane (2,2-DPANH2), 1,3-bis(4-(4-aminophenoxy)phenyl)adamantane (1,3-DPAONH2), 2,2-bis(4-(4-aminophenoxy)phenyl)adamantane (2,2-DPAONH2), 1,3-bis-(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (1,3-DPA/OH/NH2), 2,2-bis(4-(4-amino-3-hydroxyphenoxy)phenyl)adamantane (DPA) and 1,3-bis-(4-(4-amino-2-trifluoromethylphenoxy)phenyl)adamantane (1,3-DPA/CF3/NH2). Furthermore, the diaminophenyladamantane derivatives in the present invention are verified to be with great antitumor activities.